The effect of ischemic preconditioning on redox status during liver resections--randomized controlled trial.

BACKGROUND AND OBJECTIVES: Portal clamping during liver resection decreases intraoperative blood loss, but causes ischemic-reperfusion (I-R) injury. Intermittent portal clamping (IPC) and ischemic preconditioning (IP) decreased I-R injury in animal models. Most of the human studies about IP excluded cirrhotic patients, whose liver is more vulnerable to I-R injury. The effect of IP and IPC during extended liver resection was investigated in this randomized controlled trial, with special respect to cirrhotic patients. METHODS: One hundred sixty patients (100 normal liver, 60 cirrhotic) undergoing major liver resection were randomized to receive IPC (15 min ischemia, 5 min reperfusion), or IP (10 min ischemia, 10 min reperfusion). Serum oxygen-derived free radicals (ODFR) and antioxidant concentrations (preoperative, after reperfusion and 7th postoperative day), such as "conventional" liver tests (preoperative, 1st, 3rd, and 7th postoperative day) were measured. RESULTS: IP resulted in significantly lower peak ODFR, AST, ALT, and bilirubin levels after liver resection than IPC (P < 0.05). The level of serum antioxidants after reperfusion was significantly higher in IP than in IPC groups (P < 0.05). In cirrhotic patients without IP none of these values normalized until the 7th postoperative day. CONCLUSIONS: Ischemic preconditioning--especially in patients with liver cirrhosis--is a suitable method to decrease the I-R injury of the liver.

Oxidative stress with altered element content and decreased ATP level of erythrocytes in hepatocellular carcinoma and colorectal liver metastases.

Our aim was to study the possible alterations of redox status (enzymatic and nonenzymatic parameters and metal elements) in erythrocytes of patients with hepatocellular carcinoma (HCC), colorectal liver metastases (CRLM) and benign liver neoplasms. The function of redox homeostasis is closely connected to the energy level of erythrocytes, therefore, the ATP level was also determined. Antioxidant parameters, enzyme activities of superoxide dismutase and glutathione peroxidase were estimated in the erythrocytes of 11 patients with benign tumour, 23 patients with primary malignant and 37 metastatic liver tumour patients and 30 age-matched and sex-matched healthy controls. Element content with inductively coupled plasma optical emission spectrometer and ATP level by the chemiluminometric method were also determined from the samples. Free radical intensity was significantly increased, whereas erythrocyte glutathione peroxidase and superoxide dismutase activities were significantly decreased in the HCC and CRLM groups versus benign groups and controls. Se, Mn and Zn levels were lowered in HCC and CRLM groups versus benign and control groups. The content of Cu, Mg, Se and Zn changed significantly between HCC and CRLM groups. Similarly, ATP concentration decreased in HCC and CRLM versus controls and benign groups. The lowest levels of ATP and antioxidant enzyme activities were found in the case of CRLM patients. These results reveal an alteration in the ATP level of erythrocytes with concomitant changes in the antioxidant defence system in hepatic cancer patients. Altered redox homeostasis (oxidative damage) may lead to decreased ATP level and consequently may play an important role in primary carcinogenesis and generation of metastases, as well.

Alterations in the content of metal elements and fatty acids in hepatic ischaemia-reperfusion: induction of apoptotic and necrotic cell death.

Ischaemia and reperfusion are related to oxidative stress, which alters with the redox-homeostasis of the liver cells. Our aim was to reveal the correlations between changes of metal element and fatty acid concentration (two main components of redox-balance) and apoptotic and necrotic processes of hepatic ischaemia-reperfusion. Wistar rats were divided into three groups: control, sham-operated and reperfusion. Hepatic ischaemia was induced for 45 min in the left lateral, left medial and right medial lobes followed by 24 h of reperfusion. Global redox parameters and glutathione peroxidase and superoxide dismutase activity were detected by luminometry and spectrophotometry. Routine laboratory measurements, fatty acid composition (with gas chromatography) as well as metal ion concentration of liver (with ICP-OES) were determined. Metallothionein activity was measured by atomic absorption spectrometry. Immunohistochemical and histological examinations were carried out to investigate apoptotic and necrotic changes in the liver. During reperfusion, global antioxidant parameters decreased and superoxide dismutase level of the liver was significantly lower than in the sham-operated group. Changes in the metal element concentration are essential for cellular biochemical pathways, and significant correlations were found between decrease in Cu and Zn content and decreased superoxide dismutase activity. Necrotic lesions along with increased number of apoptotic cells were found in the liver after 24 h of reperfusion. Alterations in the metal element and fatty acid content was found in the liver tissue during 24 h of ischaemia-reperfusion along with increase in the number of apoptotic cells and significant disturbance of the antioxidant balance. Study of the metal element content of the liver during hepatic ischaemia-reperfusion may provide new supportive strategies for liver surgery and transplantation.

Short-term alanyl-glutamine dipeptide pretreatment in liver ischemia-reperfusion model: effects on microcirculation and antioxidant status in rats.

BACKGROUND & AIMS: Ischemia-reperfusion (I-R) injury is responsible for the morbidity associated with liver surgery. Production of toxic free radicals influences the microcirculation. The aim of our study was to examine the effect of glutamine (Gln) supplementation--adminstered in alanyl-glutamine dipeptide form--on liver function, immuno/histopathology and the oxidative state of the liver after injury. METHODS: Two-hundred and fifty grams male Wistar rats underwent normothermic, 60 min, segmental liver ischemia followed by 6 h of reperfusion. The animals (n = 45) were divided into three groups: sham operated, I-R and parenteral Gln pretreatment. Hepatic microcirculation was monitored by laser Doppler flowmetry. At the 6 h of reperfusion, histological alterations, TUNEL reaction, active caspase-3 reaction, serum and liver tissue antioxidant levels, serum ALAT, ASAT and TNF-alpha levels were measured. RESULTS: Upon reperfusion, the Gln group had significantly (p<0.05) higher flow rates than the I-R group and, at the end of the 6h of reperfusion, significantly (p<0.05) lower serum ALAT and ASAT levels. The liver chemiluminescent intensity was lower, free SH-groups were elevated, while the reducing power was decreased in the Gln-pretreated group. Positive staining for caspase-3 after Gln pretreatment was significantly increased in contrast to the control tissues. CONCLUSION: Glutamine pretreatment is beneficial in supporting hepatic microcirculation and can prevent hepatocellular necrosis in liver reperfusion injury.

The effect of ischemic preconditioning prior to intraoperative radiotherapy on ischemic and on reperfused rat liver.

BACKGROUND: The purpose of this study was to increase the tolerance of the liver to radiation injury with the proven effect of ischemic precondition (IP) in decreasing oxygen-derived free radicals, and to compare the effect of intraoperative radiotherapy (IORT) during ischemia and during reperfusion on rat liver. MATERIALS AND METHODS: Two hundred fifty to 280 g male Wistar rats underwent 45 min of normothermic, segmental liver ischemia with or without IP/5 min ischemia and 10 min reperfusion, in two cycles. During ischemia or reperfusion, IORT doses of 0, 25, or 50 Gy were applied to the ischemic liver lobe. Hepatic microcirculation was monitored by laser Doppler flowmeter. Short- and long-term histological, alkaline phosphatase, bilirubin and tumor necrosis factor-alpha levels, liver tissue, and serum antioxidant alterations were measured. RESULTS: Histological, laboratory, as well as flowmetry alterations caused by 25 Gy were reversible after 6 mo. Three mo following IORT, histological examination revealed parenchymal fibrosis, bridging, liver cell atrophy, and bile duct proliferation in the group that was irradiated with 50 Gy during reperfusion, without IP. In this group, the changes were present 6 mo following IORT, and also the levels of tumor necrosis factor-alpha and oxygen-derived free radicals after reperfusion were increased. All these changes were significantly milder in groups with IP, especially those that were irradiated during ischemia. CONCLUSIONS: IORT to the liver, up to 25 Gy, can be applied without short- or long-term treatment morbidity. Doses of up to 50 Gy are tolerated with IP, which has never been described before. Irradiation during ischemia is less toxic for the liver tissue.

Liver-protecting effects of table beet (Beta vulgaris var. rubra) during ischemia-reperfusion.

OBJECTIVE: Table beet (Beta vulgaris var. rubra) contains important bioactive agents (betaine and polyphenols), which have a wide range of physiologic effects. Because nutritive antioxidants may reduce the occurrence of complications and postoperative mortality, dietary intake of polyphenols and vitamins before surgery may greatly contribute to the survival of patients. Our aim was to determine the liver-protecting properties of bioactive substances of table beet in a model of ischemia-reperfusion injury of the rat. METHODS: Wistar rats were divided into two groups: non-treated (n = 24) and fed with table beet (n = 8). For 10 days the second group was treated with lyophilized table beet (2 g/kg body weight daily) mixed into the rat chow. Hepatic ischemia was maintained for 45 min, followed by 15 min of reperfusion. Ischemia-reperfusion was carried out on animals from both groups. Chemiluminescent intensity, H-donating ability, reducing power, free SH group concentration, Randox-total antioxidant status, glutathione peroxidase, and superoxide dismutase activities were determined by luminometry and spectrophotometry. Fatty acid (Shimadzu GC) and metal ion (inductively coupled plasma optical emission spectrometry) concentrations were observed in the liver. RESULTS: As a result of feeding, global parameters (H-donating ability, reducing power, free SH group concentration) and enzymatic antioxidants (glutathione peroxidase and superoxide dismutase) of the liver were found to increase significantly, which indicated that the treatment had a positive effect on its redox state. The increase found in zinc and copper content may protect the hepatocytes against oxidative stress because these elements are required for the function of superoxide dismutase enzymes. In the table beet group the concentration of short-chain fatty acids decreased, whereas that of long-chain fatty acids increased. The changes in metal element and fatty acid concentrations confirmed that these elements have an essential function in cellular pathways. CONCLUSION: It may be stated that a natural antioxidant-rich diet has a positive effect on redox homeostasis during hepatic ischemia-reperfusion.

Reduced antioxidant level and increased oxidative damage in intact liver lobes during ischaemia-reperfusion.

AIM: To determine whether increased blood flow of the liver can cause oxidative stress and hepatocyte damage, and to elaborate methods suitable for measuring the antioxidant defence during hepatic surgery on rat model. METHODS: In nembutal narcosis, the left lateral and the medial lobes of the liver were clipped for 45 min to make the total blood supply flow through the other lobes. Total antioxidant status, glutathione peroxidase and superoxide dysmutase activity, as well as the concentrations of diene conjugates and free sulphydril groups, H-donating ability and reducing power of the liver samples were determined. Chemiluminescent intensity of the liver was also measured. Metal ions (Al, Ca, Cu, Fe, Mg, Mn, Zn) and P and S concentrations of the liver were determined with an inductively coupled plasma optical emission spectrometer and Se content was measured by cathodic stripping voltammetry. RESULTS: Glutathione peroxidase and superoxide dysmutase activities of the liver decreased significantly in the hyperemia group compared to those observed in the sham operated group. The level of total antioxidant status was also significantly lower in the hyperemia group. H-donating ability, reducing power and free sulphydril group concentration showed the same tendency. A significant correlation (P<0.05) was found between the changes in non-specific antioxidant activities. This pointed to simultaneous activity of the antioxidant defence system. Al, Cu, Mn, Zn, and S were lower in the hyperemia group than in the sham operated group when the levels of Ca, Fe, Mg, Se and P ions were higher during hyperemia. CONCLUSION: Oxidative stress is one of the main factors for the injury of intact liver lobes during ischaemia-reperfusion.

Metal ion and antioxidant alterations in leaves between different sexes of Ginkgo biloba L.

A comparative study was carried out to determine some valuable phytochemical components, macro- and microelement and redox parameters in leaves of male and female Ginkgo biloba trees and in extracts made from them. G. biloba extracts have become more popular as a therapeutic agent in the modern pharmacology in neurodegenerative diseases, in which increased brain metal levels can be observed and free radical reactions are involved. Macro- and microelement components, total phenol content, H-donating activity and reducing power as well as total scavenger capacity were determined in the samples. Well detectable differences were obtained for micro- and macroelement contents between male and female samples, but no toxic elements could be detected in the extracts. Male extracts contained more hazardous metals (e.g. Fe) compared to the female ones, while extracts from female leaves had higher levels of ions, which are known to have beneficial effects in neurodegenerative diseases. The ethanolic extracts of male leaves showed the highest H-donating activity, reducing power and total phenol content, as well as the best total scavenger activity. Ginkgo extracts due to the antioxidant properties may have favourable effects as dietary supplements in several neurodegenerative diseases, but this study draws the attention that critical evaluation is required in view of the potential hazard induced by their metal ion constitution. Our results lead us to the conclusion that although the aqueous extracts of female leaves are characterized by relatively lower antioxidant properties, they may be more eligible for these purposes due to their favourable metal ion constitution.

[The therapeutic effect of metadoxine on alcoholic and non-alcoholic steatohepatitis]. / A metadoxin teráipiás hatásának összehasonlítása alkoholos és nem alkoholos zsírmájban.

The therapeutic effect of metadoxine on alcoholic and non-alcoholic steatohepatitis. Alcohol-induced liver disease is one of the main epidemic problems of nowadays. Non-alcoholic steatohepatitis has been described only for some years, but it also needs much more attention in the future. The etiologic factors of both entities are quite different, but the pathologic changes of the liver are nearly the same, therefore there could be certain drugs, that are equally effective in their therapy. Metadoxine is one of them, mainly because its protective effect against the damage done by free radicals. Metadoxine is a pyridoxine-pyrrolidone carboxylate with significant scavenging property. There are a lot of patients suffering from steatohepatitis, and they will face the complications of the liver damage. The aim is to provide better recovery and proper quality of life, which is based on the deeper understanding of these mechanisms. Metadoxine is suitable for increasing reduced glutathione level, which is very important for the redox homeostasis of the liver and the whole body. The effectiveness of the drug is established both in acute and in chronic alcoholism, moreover it helps in staying abstinent.

[The relationship between benign liver tumors and free radicals]. / A benignus májdaganatok és szabad gyökök kapcsolata.

The purpose of this review was to summarise what is known about the benign hepatic tumors, especially the role that free radicals play in the etiology and in the complications of these neoplasms. Nowadays benign liver tumors are considered as common entities. With the technical developments of radiology their diagnosis has become much easier, but still it is the major difficulty for the doctor to handle. There are different types of benign hepatic neoplasms: liver cyst, hemangioma, hepatocellular adenoma, focal nodular hyperplasia and there are also some rare tumor types. The relationship between hepatocellular adenoma and the use of oral contraceptives is well known. The oral contraceptives reduce the antioxidant capacity of the blood, this could be an explanation for the generation of these neoplasms. Benign liver tumors are also associated to thrombotic reactions. These neoplasms may require surgical treatment, so the oxidative stress is one of the main prognostic factors of the patients' survival.